IntroductionChemerin is a chemotactic peptide which directs leukocytes expressing the chemokine-like receptor ChemR23 towards sites of inflammation. ChemR23 is a G protein-coupled receptor which binds several different ligands, and it is also expressed by other cell types such as adipocytes. In addition to chemotaxis, recent reports suggest that ChemR23 is capable of mediating either inflammatory or anti-inflammatory effects, depending on the type of ligand it binds. In the present study, we aimed to clarify whether human chondrocytes express ChemR23 and chemerin, and whether chemerin/ChemR23 signalling could affect secretion of inflammatory mediators.MethodsTissue sections were taken from human knee joints and labelled with antibodies towards chemerin and ChemR23. Chondrocytes from cartilage tissue were isolated, cultured and assessed for chemerin and ChemR23 expression by PCR and immunolabelling. Receptor activation and intracellular signalling were studied by assessment of phosphorylated mitogen activated protein kinases (MAPKs) and phosphorylated Akt after stimulating cells with recombinant chemerin21-157. Biological effects of chemerin21-157 were investigated by measuring secretion of pro-inflammatory cytokines and metalloproteases in cell supernatants.ResultsBoth serially cultured human articular chondrocytes and resident cells in native cartilage expressed chemerin and ChemR23. Stimulating cells with chemerin21-157 resulted in phosphorylation of p44/p42 MAPKs (ERK 1/2) and Akt (Ser 473). Also, significantly enhanced levels of the pro-inflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), tumour necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and the matrix metalloproteases MMP-1, MMP-2, MMP-3, MMP-8 and MMP-13 were detected.ConclusionsThese results demonstrate that human chondrocytes express both the receptor ChemR23 and the ligand chemerin. Chemerin21-157 stimulation engaged signal-transduction pathways that further promoted inflammatory signalling in chondrocytes, as judged by an enhanced secretion of cytokines and metalloproteases. Taken together, the previously reported chemotaxis and the present findings suggest that the receptor and its ligand may play pivotal roles in joint inflammation.
We have previously demonstrated that in vivo expression of the polyomavirus DNA-binding T-antigen initiated production of IgG antibodies to T-antigen and to DNA, but not to a panel of autoantigens not related to nucleosomes, indicating an antigen-selective T cell-dependent B cell response. In this study, we demonstrate that CD4-positive T cells from both normal and systemic lupus erythematosus (SLE) patients readily proliferate in response to pure T-antigen, and also to T-antigen in complex with nucleosomes. T-antigen-specific T cell lines from both normal individuals and SLE patients proliferate in response to nucleosome-T-antigen complexes, but not to nucleosomes or histones. B cells co-cultured with T-antigen-specific T cells and stimulated with nucleosome-T-antigen complexes produce anti-T-antigen and anti-DNA antibodies, indicating that such CD4-positive T cells have the potential to interact with B cells specific for individual components of nucleosome-T-antigen complexes. Thus, a non-self DNA-binding protein like polyomavirus T-antigen may initiate and maintain an antibody response to DNA when T-antigen is actively expressed.
We have previously demonstrated that in vivo expression of the polyomavirus DNA‐binding T‐antigen initiated production of IgG antibodies to T‐antigen and to DNA, but not to a panel of autoantigens not related to nucleosomes, indicating an antigen‐selective T cell‐dependent B cell response. In this study, we demonstrate that CD4‐positive T cells from both normal and systemic lupus erythematosus (SLE) patients readily proliferate in response to pure T‐antigen, and also to T‐antigen in complex with nucleosomes. T‐antigen‐specific T cell lines from both normal individuals and SLE patients proliferate in response to nucleosome‐T‐antigen complexes, but not to nucleosomes or histones. B cells co‐cultured with T‐antigen‐specific T cells and stimulated with nucleosome‐T‐antigen complexes produce anti‐T‐antigen and anti‐DNA antibodies, indicating that such CD4‐positive T cells have the potential to interact with B cells specific for individual components of nucleosome‐T‐antigen complexes. Thus, a non‐self DNA‐binding protein like polyomavirus T‐antigen may initiate and maintain an antibody response to DNA when T‐antigen is actively expressed.
Objective. Investigators in this study undertook to determine whether in vitro antigen-responsive immune (polyomavirus T antigen [T-ag]-specific) and autoimmune (histone-specific) T cells from normal individuals share structural and genetic characteristics with those from patients with systemic lupus erythematosus (SLE).Methods. Histone-specific T cells were generated by stimulation of peripheral blood mononuclear cells (PBMCs) with nucleosome-T-ag complexes and were subsequently maintained by pure histones. T-agspecific T cell clones were initiated and maintained by T-ag. The frequencies of circulating histone-and T-agspecific T cells were determined in healthy individuals and in SLE patients by limiting dilution of PBMCs. T cell receptor (TCR) gene usage and variable-region structures were determined by complementary DNA sequencing. These sequences were compared between T-ag-and histone-specific T cells and between normal individuals and SLE patients for each specificity.Results. Individual in vitro-expanded histoneand T-ag-specific T cells from normal individuals displayed identical TCR V ␣ and/or V  chain third complementarity-determining region (CDR3) sequences, indicating that they were clonally expanded in vivo. The frequencies of in vitro antigen-responsive T-ag-or histone-specific T cells from normal individuals were similar to those from SLE patients. Although heterogeneous for variable-region structure and gene usage, histone-specific T cells from healthy individuals and SLE patients selected aspartic and/or glutamic acids at positions 99 and/or 100 of the V  CDR3 sequence. Conclusion. Autoimmune T cells from healthy individuals can be activated by nucleosome-T-ag complexes and maintained by histones in vitro. Such T cells possessed TCR structures similar to those from SLE patients, demonstrating that T cell autoimmunity to nucleosomes may be a latent property of the normal immune system.Experimental results consistently demonstrate that pathogenic autoimmune anti-DNA antibodies are secondary, antigen-driven, CD4ϩ T cell-dependent immune responses initiated by DNA itself (1-5). Since DNA most likely is not presented by antigen-presenting cells (APCs) in the context of HLA class II molecules, the contemporary paradigm favors DNA binding proteins as a sine qua non for generating T helper cell stimuli in the autoimmune anti-DNA antibody response (3,5,6). Such a hapten-carrier model, implying DNAspecific B cells and protein-specific T cells, enables the understanding of the molecular and the cellular basis for an immunoglobulin class switch and affinity maturation of anti-single-stranded DNA and anti-double-stranded DNA (anti-dsDNA) antibodies. Experimental and clinical results demonstrating that T cells specific for self or non-self DNA binding proteins may provide help for DNA-specific B cells support a model consistent with cognate B cell-T cell interaction (2,3,(6)(7)(8). So far, however, it is unclear how self-specific T cells may be initially activated. A priori, one would expect, for example, nuc...
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